BD2-selective BRD4 inhibitor ZX29 mitigates myocardial ischemia-reperfusion injury via BRD4-YY1-NCOA4 axis disruption and ferroptosis inhibition.
- 1National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Guangdong Province Engineering Laboratory for Druggability and New Drug Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
- 2Department of Cardiac Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
- 3School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China.
Abstract
Myocardial ischemia/reperfusion injury (MI/RI) remains a major barrier to ischemic heart disease treatment, as reperfusion therapies often exacerbate cardiac damage. Bromodomain-containing protein 4 (BRD4) is a key epigenetic target in cardiovascular diseases, but pan-BRD4 inhibitors cause severe off-target toxicity by disrupting basal bromodomain 1 (BD1) function, highlighting the need for BD2-selective agents. This study aimed to develop a BD2-selective BRD4 inhibitor and clarify its mechanism. ZX29 was developed via virtual screening of 100,000 compounds and structure-based optimization, exhibiting potent BRD4 binding with an IC₅₀ of 0.27 ± 0.03 μmol/L and K d of 1.68 μmol/L, outperforming clinical agent RVX-208. ZX29 specifically binds BRD4 BD2 via H437/V439 residues. In murine MI/RI models, oral ZX29 significantly improved cardiac systolic and diastolic function, reduced myocardial infarct size, and mitigated lipid peroxidation. Mechanistically, ZX29 disrupted the BRD4-Yin Yang 1 (YY1) interaction and inhibited the nuclear receptor coactivator 4 (NCOA4)-ferritin heavy chain 1 (FTH1) degradation axis, suppressing lysosomal ferrous iron release and ferroptosis. Moreover, ZX29 preserved mitochondrial function by maintaining mitochondrial membrane potential and boosting ATP production. Ultimately, this study validates selective BRD4 BD2 inhibition as a safe and effective therapeutic strategy for MI/RI and establishes ZX29 as a viable clinical candidate.
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BibTeX
@article{li2026bd2selective,
title = {{BD2-selective BRD4 inhibitor ZX29 mitigates myocardial ischemia-reperfusion injury via BRD4-YY1-NCOA4 axis disruption and ferroptosis inhibition.}},
author = {Zeyu Li and Meixiu Xin and Zhongkai Wu and Jing Lu and Ou Hu and Yong Zou and Peiqing Liu},
journal = {Acta pharmaceutica Sinica. B},
year = {2026},
month = jul,
doi = {10.1016/j.apsb.2026.07.043},
url = {https://europepmc.org/article/MED/42948426},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - BD2-selective BRD4 inhibitor ZX29 mitigates myocardial ischemia-reperfusion injury via BRD4-YY1-NCOA4 axis disruption and ferroptosis inhibition.
AU - Zeyu Li
AU - Meixiu Xin
AU - Zhongkai Wu
AU - Jing Lu
AU - Ou Hu
AU - Yong Zou
AU - Peiqing Liu
PY - 2026
DA - 2026/07/30
JO - Acta pharmaceutica Sinica. B
DO - 10.1016/j.apsb.2026.07.043
UR - https://europepmc.org/article/MED/42948426
AB - Myocardial ischemia/reperfusion injury (MI/RI) remains a major barrier to ischemic heart disease treatment, as reperfusion therapies often exacerbate cardiac damage. Bromodomain-containing protein 4 (BRD4) is a key epigenetic target in cardiovascular diseases, but pan-BRD4 inhibitors cause severe off-target toxicity by disrupting basal bromodomain 1 (BD1) function, highlighting the need for BD2-selective agents. This study aimed to develop a BD2-selective BRD4 inhibitor and clarify its mechanism. ZX29 was developed via virtual screening of 100,000 compounds and structure-based optimization, exhibiting potent BRD4 binding with an IC₅₀ of 0.27 ± 0.03 μmol/L and K d of 1.68 μmol/L, outperforming clinical agent RVX-208. ZX29 specifically binds BRD4 BD2 via H437/V439 residues. In murine MI/RI models, oral ZX29 significantly improved cardiac systolic and diastolic function, reduced myocardial infarct size, and mitigated lipid peroxidation. Mechanistically, ZX29 disrupted the BRD4-Yin Yang 1 (YY1) interaction and inhibited the nuclear receptor coactivator 4 (NCOA4)-ferritin heavy chain 1 (FTH1) degradation axis, suppressing lysosomal ferrous iron release and ferroptosis. Moreover, ZX29 preserved mitochondrial function by maintaining mitochondrial membrane potential and boosting ATP production. Ultimately, this study validates selective BRD4 BD2 inhibition as a safe and effective therapeutic strategy for MI/RI and establishes ZX29 as a viable clinical candidate.
SN - 2211-3835
SN - 2211-3843
ER -